Deep Venous Thrombosis (DVT)

Definitions

Anatomic Site of Deep Venous Thrombosis

  • Proximal Deep Venous Thrombosis: involves iliac, femoral, or popliteal veins
  • Distal (Calf) Deep Venous Thrombosis: involves crural calf veins (anterior tibial vein, posterior tibial vein, peroneal vein) or muscular calf veins (gastrocnemius vein, soleal vein, or other muscular calf vein)

Provoked vs Unprovoked Deep Venous Thrombosis

  • Provoked Deep Venous Thrombosis: deep venous thrombosis attributable to an identifiable etiology or provoking event
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Estrogen Therapy (see Estrogen, [[Estrogen]])
    • Hospital Admission
    • Inheritable Hypercoagulable State (see Hypercoagulable States, [[Hypercoagulable States]])
    • Malignancy
    • Pregnancy (see Pregnancy, [[Pregnancy]])
    • Prolonged Immobility
    • Surgery
  • Unprovoked Deep Venous Thrombosis: deep venous thrombosis with no identifiable etiology or provoking event

Symptomatic vs Asymptomatic Deep Venous Thrombosis

  • Asymptomatic Deep Venous Thrombosis: DVT diagnosed with a lack of clinical symptoms (ie incidentally diagnosed on radiologic study performed in an asymptomatic patient)
  • Symptomatic Deep Venous Thrombosis: presence of clinical symptoms that would lead to the radiologic diagnosis of DVT

Epidemiology

Risk of Deep Venous Thrombosis in Mechanically-Ventilated Patients


Risk Factors for Venous Thromboembolism

General Comments

  • Same Risk Factors as for Deep Venous Thrombosis (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
    • Risk Factor Can Be Identified in >80% of Patients with Venous Thrombosis: more than one factor may often be present
      • 50% of thrombotic events in patients with inherited hypercoagulable states are associated with an additional risk factor (pregnancy, surgery, prolonged immobilization, oral contraceptives)

Inherited Risk Factors (see Hypercoagulable States, [[Hypercoagulable States]])

  • General Comments
    • Factor V Leiden gene mutation and prothrombin gene mutation account 50-60% of inherited (primary) hypercoagulable states
  • Antithrombin Deficiency (see Antithrombin Deficiency, [[Antithrombin Deficiency]])
  • Dysfibrinogenemia (see Dysfibrinogenemia, [[Dysfibrinogenemia]]): rare
  • Factor V Leiden (see Factor V Leiden, [[Factor V Leiden]])
  • Factor XII Deficiency (see xxxx, [[xxxx]])
  • Family History of Venous Thromboembolism: strong risk factor
  • Heparin Cofactor II Deficiency: unclear risk factor
  • Plasminogen Deficiency: unclear risk factor
  • Protein C Deficiency (see Protein C Deficiency, [[Protein C Deficiency]])
  • Protein S Deficiency (see Protein S Deficiency, [[Protein S Deficiency]])
  • Prothrombin Gene Mutation (see Prothrombin Gene Mutation, [[Prothrombin Gene Mutation]])

Acquired Risk Factors (see Hypercoagulable States, [[Hypercoagulable States]])

  • Active Tuberculosis (see Tuberculosis, [[Tuberculosis]])
  • Age: hazard ratio of 1.7 (95 percent confidence interval: 1.5 to 2.0) for every decade of life after age 55 (ARIC and CHS studies)
  • Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]])
  • Asthma (see Asthma, [[Asthma]])
  • Bevacizumab (Avastin) (see Bevacizumab, [[Bevacizumab]])
    • Clinical: increased risk of venous and arterial events
  • Central Intravenous Catheters
  • Chronic Kidney Disease (CKD), Especially with Hemodialysis (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
  • Chronic Myeloproliferative Diseases (see Chronic Myeloproliferative Diseases, [[Chronic Myeloproliferative Diseases]])
    • Myeloproliferative Neoplasms
      • Essential Thrombocythemia (see Essential Thrombocythemia, [[Essential Thrombocythemia]])
      • Polycythemia Vera (see Polycythemia Vera, [[Polycythemia Vera]])
        • Physiology: hyperviscosity and qualitative platelet defects
  • Chronic Psoriasis (see Psoriasis, [[Psoriasis]])
  • Congenital Venous Malformation of the Inferior Vena Cava
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
  • Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
  • Erythropoiesis-Stimulating Agents
  • Glucocorticoids (see Corticosteroids, [[Corticosteroids]]): data come from a Dutch population-based case-control study of 38,765 Danish adults who developed venous thromboembolism in a 7-year period, compared with 387,650 controls [MEDLINE]
    • Systemic vs Non-Systemic Steroids: risk of venous thromboembolism was highest with use of systemic glucocorticoids, as compared to a relatively lower risk with inhaled or gastrointestinal glucocorticoids
    • Time of Onset-Related Effect: risk of venous thromboembolism was highest with new use of glucocorticoids (incidence ratio 3.06), as compared to continuing or past use
    • Dose-Effect: risk of venous thromboembolism increased with increasing cumulative doses of the glucocorticoids
    • Possible Study Flaws: study may not have been able to fully account for all of the confounding risks of venous thrombombolism related to the underlying disease itself (for which the steroids were prescribed): the underlying disease may have increased the risk of venous thromboembolism or the increased risk of immobility (which could indirectly increase the risk of venous thromboembolism)
  • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
  • Hormone Replacement Therapy (see Estrogen, [[Estrogen]])
  • Hyperhomocysteinemia (see Hyperhomocysteinemia, [[Hyperhomocysteinemia]])
  • Hypertension (see Hypertension, [[Hypertension]])
  • Hyperviscosity States (see Hyperviscosity, [[Hyperviscosity]])
    • Hyperfibrinogenemia
    • Waldenstrom’s Macroglobulinemia: due to hypergammaglobulinemia
    • Multiple Myeloma: due to hypergammaglobulinemia
    • Leukostasis (see Leukostasis, [[Leukostasis]])
    • Sickle Cell Disease (see Sickle Cell Disease, [[Sickle Cell Disease]])
  • Immobilization
    • Bedrest
    • Extended Travel
    • Lower Extremity Fracture/Injury
  • Inflammatory Bowel Disease (see Inflammatory Bowel Disease, [[Inflammatory Bowel Disease]])
  • Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, [[Intravenous Drug Abuse]]): due to femoral injection of drugs
  • Lenalidomide (Revlimid) (see Lenalidomide, [[Lenalidomide]])
  • Liver Disease (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
    • Epidemiology: there is a high (6.3%) risk of venous thromboembolism in hospitalized liver disease patients, despite abnormal coagulation parameters [MEDLINE]
  • Lower Extremity Venous Insufficiency
  • Malignancy: clinical venous thromboembolism occurs in 5% of patients with cancer
    • Co-Incidence of DVT and Malignancy: 20% of patients with DVT have a known active malignancy
    • Risk of Venous Thrombembolism in Course of Cancer: highest risk during initial hospitalization, at the onset of chemotherapy, and at the time of disease progression
    • Presence of a Central Venous Catheter: futher compounds the risk of malignancy-associated venous thromboembolism
    • Common Sites of Malignancies at Time of Venous Thromboembolism Diagnosis: most cancers (78%) are diagnosed before the diagnosis of the DVT
      • Lung Cancer: 17%
      • Pancreatic Cancer: 10%
      • Colorectal cancer: 8%
      • Renal Cancer: 8%
      • Prostate Cancer: 7%
  • May-Thurner Syndrome
    • Physiology: compression of the left common iliac vein between the overlying right common iliac artery and underlying vertebral body
  • Nephrotic Syndrome (see Nephrotic Syndrome, [[Nephrotic Syndrome]])
  • Non-Steroidal Anti-Inflammatory Drugs (NSAID’s) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal Anti-Inflammatory Drug]])
    • Epidemiology
      • Systematic Review and Meta-analysis (Rheumatology, 2015) [MEDLINE]: NSAID’s increase risk of venous thromboembolism with RR of 1.80 (95% CI: 1.28-2.52)
  • Obesity with BMI ≥29 kg/m2 (see Obesity, [[Obesity]])
  • Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]])
  • Oral Contraceptives (OCP) (see Oral Contraceptives, [[Oral Contraceptives]])
  • Ovarian Hyperstimulation Syndrome (see Ovarian Hyperstimulation Syndrome, [[Ovarian Hyperstimulation Syndrome]])
  • Paget-Schroetter Syndrome (see Paget-Schroetter Syndrome, [[Paget-Schroetter Syndrome]])
    • Physiology: underlying venous compression at the thoracic outlet
  • Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria, [[Paroxysmal Nocturnal Hemoglobinuria]])
  • Pregnancy (see Pregnancy, [[Pregnancy]])
    • Incidence of DVT is equal throughout pregnancy (first trimester: 22%/second trimester: 41%/third trimester: 37%)
    • Incidence of PE during pregnancy: 34% occur pre-partum, 66% occur post-partum (82% of these follow C-section)
    • Increased risk of DVT in left leg during pregnancy (possibly due to left common iliac vein compression by overlying right iliac artery)
    • ASA does not affect risk of DVT in pregnancy (even in presence of anti-phospholipid Ab syndrome)
  • Polycystic Ovary Syndrome (see Polycystic Ovary Syndrome, [[Polycystic Ovary Syndrome]])
  • Presence of Central Venous Catheter (CVC) (see Central Venous Catheter, [[Central Venous Catheter]])
  • Prior Thrombotic Event: major risk factor
  • Prothrombin Complex Concentrate-3 Factor (Profilnine SD) (see Prothrombin Complex Concentrate-3 Factor, [[Prothrombin Complex Concentrate-3 Factor]])
  • Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor, [[Prothrombin Complex Concentrate-4 Factor]])
  • Recent Arterial Cardiovascular Event (Within 3 Months): short-term increase in venous thromboembolism risk
  • Recent Major Surgery
    • Cancer Surgery
    • Major Vascular Surgery
    • Neurosurgery
    • Orthopedic Surgery
      • Total Hip Replacement: 30-day risk of symptomatic non-fatal venous thromboembolism is 2.5% [MEDLINE][MEDLINE]
      • Total Knee Replacement: 30-day risk of symptomatic non-fatal venous thromboembolism is 1.4% [MEDLINE][MEDLINE]
  • Renal Transplant (see Renal Transplant, [[Renal Transplant]])
  • Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis, [[Rheumatoid Arthritis]])
  • Sepsis (see Sepsis, [[Sepsis]])
  • Superficial Thrombophlebitis/Superficial Venous Thrombosis (SVT) (see Superficial Venous Thrombosis, [[Superficial Venous Thrombosis]])
    • Epidemiology: SVT may occur in patients with inherited/acquired hypercoagulable states
    • Clinical
      • Occult DVT: occult DVT is present in 7-32% of superficial thrombophlebitis cases (suggests that screening of these patients with LE dopplers may be warranted)
      • Recurrence of SVT: 24% of cases have recurrent SVT [MEDLINE]
      • Later Development of DVT: 32% of SVT cases develop DVT at median interval of 4 years [MEDLINE]
  • Tamoxifen (see Tamoxifen, [[Tamoxifen]])
  • Testosterone (see Testosterone, [[Testosterone]])
  • Thalidomide (see Thalidomide, [[Thalidomide]])
  • Tobacco Abuse (see Tobacco, [[Tobacco]]): cigarette smoking >25 cigarettes per day increases risk
  • Trauma of Any Etiology
    • Physiology: decreased lower extremity venous blood flow, decreased fibrinolysis, and immobilization

Lower Extremity Venous Anatomy

Superficial Veins

  • Greater Saphenous Vein Above or Below the Knee
  • Non-Saphenous Veins
  • Small Saphenous Vein
  • Telangiectasias/Reticular Veins

Deep Veins

  • Inferior Vena Cava (IVC)
  • Iliac Veins
    • Common Iliac Vein
    • External Iliac Vein
    • Internal Iliac Vein
  • Pelvic Veins
    • Broad Ligament Vein
    • Gonadal Vein
    • Other Pelvic Veins
  • Femoral Veins
    • Common Femoral Vein
    • Deep Femoral Vein
  • Popliteal Vein
  • Crural Calf Veins
    • Anterior Tibial Vein: less common site of distal DVT
    • Posterior Tibial Vein: more common site of distal DVT
    • Peroneal Vein: more common site of distal DVT
  • Muscular Calf Veins: less common site of distal DVT
    • Gastrocnemius Vein
    • Soleal Vein
    • Other Muscular Calf Veins

Perforator Veins

  • Thigh Perforator Vein
  • Calf Perforator Vein

Upper Extremity Venous Anatomy

Superficial Veins

  • Basilic Vein
    • Common site of PICC placement
  • Cephalic Vein
  • Median Antebrachial Vein
  • Median Antecubital Vein
  • Accessory Cephalic Vein

Deep Veins

  • Radial Vein
  • Ulnar Vein
  • Interosseous Vein: in the forearm
  • Brachial Vein
    • Common site for PICC-related DVT
  • Axillary Vein
    • Common site for PICC-related DVT
  • Subclavian Vein
    • Common site for PICC-related DVT
  • Internal Jugular Vein
    • Most common site for CVC-related deep venous thrombosis

Physiology

Upper Extremity Deep Venous Thrombosis

Lower Extremity Deep Venous Thrombosis

  • Calf Vein (Distal) DVT
    • Progression: left untreated, distal DVT will progress to proximal DVT in approximately 33% of cases
      • Usually progresses within the first 2 wks after diagnosis: if extension does not occur in the first 2 wks, it is unlikely to occur
      • Limited muscular calf vein distal DVT has a low risk of extension without treatment (risk of extension: 3%), as compared to extensive thrombosis of multiple calf veins (risk of extension: 15%)
    • Risk of Pulmonary Embolism with Distal DVT: risk of distal DVT embolization is approximately 50% the risk of proximal DVT embolization [MEDLINE]
  • Proximal DVT

Diagnosis

D-Dimer (see D-Dimer, [[D-Dimer]])

  • Advantages
    • Easy to Obtain
  • Disadvantages
    • May Be Elevated in Conditions Other Than Venous Thromboembolism

Lower Extremity Compression Venous Doppler Ultrasound (see Lower Extremity Venous Doppler Ultrasound, [[Lower Extremity Venous Doppler Ultrasound]])

  • Advantages
    • Allows for Evaluation of Superficial and Deep Venous Systems
    • Easily Repeated
    • Non-Invasive
  • Accuracy
    • Sensitivity: xxx
    • Specificity: xxx
  • Recommendations: see below

Upper Extremity Compression Venous Doppler Ultrasound (see Upper Extremity Venous Doppler Ultrasound, [[Upper Extremity Venous Doppler Ultrasound]])

  • Advantages
    • Allows for Evaluation of Superficial and Deep Venous Systems
    • Easily Repeated
    • Non-Invasive
  • Accuracy
    • Sensitivity: 91% (with large confidence intervals)
    • Specificity: 93% (with large confidence intervals)
  • Recommendations: see below

Computed Tomography (CT) Lower Extremity Venogram (see Computed Tomography Lower Extremity Venogram, [[Computed Tomography Lower Extremity Venogram]])

  • Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • CT Venogram is an Alternative to Compression Lower Extremity Venous Doppler Ultrasound When Ultrasound is Impractical (Patients with Lower Extremity Casting, Significant Lower Extremity Edema or Wounds, etc)

Computed Tomography (CT) Upper Extremity Venogram (see Computed Tomography Upper Extremity Venogram, [[Computed Tomography Upper Extremity Venogram]])

  • Recommendations for Diagnostic Testing Suspected Upper Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Upper Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • If Upper Extremity Compression Venous Doppler Ultrasound is Negative with High Clinical Suspicion, Moderate/High-Sensitivity D-Dimer, Serial Ultrasound, CT Upper Extremity Venogram, or Gadolinium-Enhanced Magnetic Resonance Upper Extremity MRI Venogram is Recommended (Grade 2C Recommendation)

Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram and Pulmonary Angiogram (MRA) (see Magnetic Resonance Lower Extremity Venogram, [[Magnetic Resonance Lower Extremity Venogram]] and Magnetic Resonance Pulmonary Angiogram, [[Magnetic Resonance Pulmonary Angiogram]])

  • Advantages
    • No Exposure to Iodinated Radiographic Contrast
    • No Radiation Exposure
      May Be Used as an Alternative to Compression Lower Extremity Venous Doppler Ultrasound When Ultrasound is Impractical (Patients with Lower Extremity Casting, Significant Lower Extremity Edema or Wounds, etc)
  • Disadvantages
    • Magnetic Resonance Venogram and Pulmonary Angiogram Have High Rates of Technically Inadequate Studies [MEDLINE]: technically inadequate studies were found in 25% (range: 11-52%) of studies performed in the PIOPED III Study (2010), depending on the center
      • Due to the large number of technically inadequate studies in PIOPED III, magnetic resonance venography and pulmonary angiogram only identified 57% of patients with pulmonary embolism
      • Vascular opacification and motion artifact are the principal factors which influence interpretability of MRA [MEDLINE]: some centers appear to obtain better images (for unclear reasons)
    • Technically Adequate Magnetic Resonance Pulmonary Angiogram
      • Sensitivity: 78%
      • Specificity: 99%
    • Technically Adequate Magnetic Resonance Pulmonary Angiogram + Magnetic Resonance Venogram: combination has significantly higher sensitivity than magnetic resonance pulmonary angiogram alone (however, only 52% of patients had technically inadequate results)
      • Sensitivity: 92%
      • Specificity: 96%
  • Recommendations
    • Magnetic Resonance Pulmonary Angiogram and Venogram Studies Should Only be Performed in Centers with Local Expertise

Gadolinium-Enhanced Magnetic Resonance Upper Extremity Venogram (see Magnetic Resonance Upper Extremity Venogram, [[Magnetic Resonance Upper Extremity Venogram]])

  • Recommendations for Diagnostic Testing Suspected Upper Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Upper Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • If Upper Extremity Compression Venous Doppler Ultrasound is Negative with High Clinical Suspicion, Moderate/High-Sensitivity D-Dimer, Serial Ultrasound, CT Upper Extremity Venogram, or Gadolinium-Enhanced Magnetic Resonance Upper Extremity MRI Venogram is Recommended (Grade 2C Recommendation)

Lower Extremity Venogram (see Lower Extremity Venogram, [[Lower Extremity Venogram]])

  • Indications: gold standard for diagnosis of lower extremity DVT
  • Rarely Performed Today

Lower Extremity Impedance Plethysmography (IPG)

  • Indications: sensitive for above the knee DVT

Lower Extremity Radiofibrinogen Study

  • Indications: sensitive for calf/lower thigh DVT

Recommendations for Diagnostic Testing for Suspected Lower Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

Recommended Diagnostic Testing for Suspected First Lower Extremity Deep Venous Thrombosis if Risk Stratification is NOT USED to Classify Patient (By Pretest Probability)

  • Recommendations for Diagnostic Testing for Patients with No Risk Stratification with First Lower Extremity DVT (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Proximal or Whole Leg Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 1B Recommendation vs No Testing, Grade 2B vs D-Dimer Testing)
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
      • Not Recommended as the Routine Initial Diagnostic Test (Grade 1C Recommendation)
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
      • Not Recommended as the Routine Initial Diagnostic Test (Grade 1C Recommendation)

Recommended Diagnostic Testing for Suspected First Lower Extremity Deep Venous Thrombosis if Risk Stratification is USED to Classify Patient (By Pretest Probability)

  • Recommendations for Diagnostic Testing for Patients with Low Pretest Probability of First Lower Extremity DVT (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]: one of the following
    • Moderate-Sensitivity D-Dimer (Grade 1B Recommendation): D-dimer is the preferred initial diagnostic test if there are no comorbid conditions which might be expected to elevate the D-dimer (Grade 2C Recommendation)
      • If D-Dimer is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If D-Dimer is Positive, Compression Proximal Lower Extremity Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • High-Sensitivity D-Dimer (Grade 1B Recommendation): D-dimer is the preferred initial diagnostic test if there are no comorbid conditions which might be expected to elevate the D-dimer (Grade 2C Recommendation)
      • If D-Dimer is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If D-Dimer is Positive, Compression Proximal Lower Extremity Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • Proximal Lower Extremity Compression Venous Doppler Ultrasound (Grade 1B Recommendation): ultrasound is the preferred initial diagnostic test if there are comorbid conditions which might be expected to elevate the D-dimer
      • If Proximal Ultrasound is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
  • Recommendations for Diagnostic Testing for Patients with Moderate Pretest Probability of First Lower Extremity DVT (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]: one of the following
    • High-Sensitivity D-Dimer (Grade 1B Recommendation): high-sensitivity D-dimer is the preferred initial diagnostic test if there are no comorbid conditions which might be expected to elevate the D-dimer (Grade 2C Recommendation)
      • If D-Dimer is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If D-Dimer is Positive, Proximal or Whole Leg Ultrasound is Recommended (Grade 1B Recommendation)
    • Proximal or Whole Leg Lower Extremity Compression Venous Doppler Ultrasound (Grade 1B Recommendation): ultrasound is the preferred initial diagnostic test if there are comorbid conditions which might be expected to elevate the D-dimer
      • If Proximal Ultrasound is Performed First and is Negative, Moderate/High-Sensitivity D-Dimer Immediately or Repeat Ultrasound in 7 Days is Recommended (Grade 1C Recommendation)
      • If Proximal Ultrasound is Negative, But D-Dimer is Positive, Repeat Ultrasound in 7 Days is Recommended (Grade 1B Recommendation)
      • If Whole Leg Ultrasound is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
      • If Isolated Distal DVT is Detected, Serial Lower Extremity Ultrasound to Rule Out Proximal Extension is Recommended (Grade 2C Recommendation): patients with severe symptoms and risk factors for extension are more likely to benefit from treatment over repeat ultrasound (see treatment below)
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
  • Recommendations for Diagnostic Testing for Patients with High Pretest Probability of First Lower Extremity DVT (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Moderate/High-Sensitivity D-Dimer Should Not Be Used as Standalone Tests in Patients with High Pretest Probability of DVT (Grade 1B Recommendation)
    • Proximal or Whole Leg Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 1B Recommendation)
      • Whole Leg Ultrasound is Preferred Over Proximal Ultrasound in Patients Who are Unable to Return for Serial Lower Extremity Ultrasound Testing and Those with Severe Symptoms Consistent with Distal DVT
    • CT Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • Gadolinium-Enhanced Magnetic Resonance Lower Extremity Venogram: may be alternatively used when lower extremity venous ultrasound is not practical or possible
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Repeat Proximal/Whole Leg Lower Extremity Compression Venous Doppler Ultrasound or High Sensitivity D-Dimer in 7 Days is Recommended (Grade 1B Recommendation)
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, But D-Dimer is Positive, Repeat Proximal/Whole Leg Lower Extremity Compression Venous Doppler Ultrasound in 7 Days is Recommended (Grade 1B Recommendation)
    • If Whole Leg Lower Extremity Compression Venous Doppler Ultrasound is Negative, No Further Testing is Recommended (Grade 1B Recommendation)
    • If Unexplained Lower Extremity Swelling is Present with Negative Lower Extremity Ultrasound and Negative/Positive D-Dimer, Iliac Veins Should Be imaged to Exclude Isolated Iliac Vein DVT

Recommended Diagnostic Testing for Suspected Recurrent Lower Extremity Deep Venous Thrombosis

  • Recommendations for Diagnostic Testing for Patients with Recurrent Lower Extremity DVT (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Proximal Lower Extremity Compression Venous Doppler Ultrasound or High-Sensitivity D-Dimer is Recommended (Grade 1B Recommendation)
    • If High-Sensitivity D-Dimer is Positive, Proximal Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 1B Recommendation)
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Repeat Proximal Lower Extremity Compression Venous Doppler Ultrasound or High-Sensitivity D-Dimer in 7 Days is Recommended (Grade 1B Recommendation)

Recommended Diagnostic Testing for Suspected Pregnancy-Associated Lower Extremity Deep Venous Thrombosis

  • Recommendations for Diagnostic Testing for Pregnant Patients with Suspected Lower Extremity DVT (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Proximal Lower Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • If Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Repeat Proximal Lower Extremity Compression Venous Doppler Ultrasound in 3 and 7 Days (Grade 1B Recommendation) or Sensitive D-Dimer at Time of Presentation (Grade 2B Recommendation) is Recommended
    • If Isolated Iliac Vein DVT is Suspected, But Proximal Lower Extremity Compression Venous Doppler Ultrasound is Negative, Ultrasound of Iliac Vein (Grade 2C Recommendation), Venography (Grade 2C Recommendation), or Direct MRI (Grade 2C Recommendation) is Recommended

Recommendations for Diagnostic Testing for Suspected Upper Extremity Deep Venous Thrombosis

  • Recommendations for Diagnostic Testing Suspected Upper Extremity Deep Venous Thrombosis (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Upper Extremity Compression Venous Doppler Ultrasound is Recommended (Grade 2C Recommendation)
    • If Upper Extremity Compression Venous Doppler Ultrasound is Negative with High Clinical Suspicion, Moderate/High-Sensitivity D-Dimer, Serial Ultrasound, CT Upper Extremity Venogram, or Gadolinium-Enhanced Magnetic Resonance Upper Extremity MRI Venogram is Recommended (Grade 2C Recommendation)
  • Clinical Use of Diagnostic Algorithms in Upper Extremity Deep Venous Thrombosis
    • Use of Diagnostic Algorithm for Upper Extremity DVT (2014) [MEDLINE]
      • Study: multi-center international study (n = 406 inpatients) in Europe/US using algorithm with sequential application of a clinical decision score, D-dimer testing, and ultrasonography
      • Main Findings: combination of a clinical decision score, D-dimer testing, and ultrasonography can safely and effectively exclude the diagnosis of upper extremity DVT

Clinical Manifestations of Lower Extremity Deep Venous Thrombosis

Rheumatologic/Orthopedic Manifestations

Lower Extremity Pain (see Lower Extremity Pain, [[Lower Extremity Pain]])

  • xxxxx

Peripheral Edema (see Peripheral Edema, [[Peripheral Edema]])

  • xxxx

Phlegmasia Cerulea Dolens

  • Epidemiology
    • Age: peak in 5th-6th decade of life
    • Sex: F>M
  • Precipitating Factors
    • Idiopathic (10% of cases)
    • Inferior Vena Cava (IVC) Filter Insertion (see Inferior Vena Cava Filter, [[Inferior Vena Cava Filter]])
    • Inherited Hypercoagulable State (see Hypercoagulable States, [[Hypercoagulable States]])
    • Malignancy (20-40% of cases): most common precipitating factor
    • Pregnancy (see Pregnancy, [[Pregnancy]])
    • Surgery
    • Trauma
  • Physiology: acute massive proximal (iliofemoral) venous thrombosis with obstructed venous drainage of lower extremity -> may result in arterial compression and acute limb ischemia (see Acute Limb Ischemia, [[Acute Limb Ischemia]])
    • Left Lower Extremity Involvement: left lower extremity is involved 3-4x as often as the right lower extremity
    • Upper Extremity Involvement: upper extremity involvement occurs in <5% of cases
  • Clinical Manifestations
    • Blebs/Bullous Skin Lesions (see Vesicular-Bullous Skin Lesions, [[Vesicular-Bullous Skin Lesions]])
    • Peripheral Edema (see Peripheral Edema, [[Peripheral Edema]])
    • Cyanosis (Cerulea) (see Cyanosis, [[Cyanosis]]): usually a characteristic finding
      • Progresses from distal to proximal lower extremity
    • Phlegmasia Alba Dolens: blanching (alba) without cyanosis
    • Sudden Onset of Severe Lower Extremity Pain (see Lower Extremity Pain, [[Lower Extremity Pain]]): pain is usually constant and severe (usually starts at the femoral triangle and progresses to involve the entire lower extremity)
      • Symptoms may be gradual in onset in some cases
    • Venous Gangrene: late finding
    • Compartment Syndrome (see Compartment Syndrome, [[Compartment Syndrome]])

Post-Thrombotic (Post-Phlebitic) Syndrome

  • Epidemiology
  • Clinical
    • xxxx

Other Manifestations

  • xxx

Clinical Manifestations of Upper Extremity Deep Venous Thrombosis

Rheumatologic/Orthopedic Manifestations

Upper Extremity Pain (see Upper Extremity Pain, [[Upper Extremity Pain]])

  • xxxxx

Upper Extremity Peripheral Edema (see Peripheral Edema, [[Peripheral Edema]])

  • xxxx

DVT Prophylaxis

High-Risk Medical Patients

Methods of Deep Venous Thrombosis Prophylaxis in High-Risk Medical Patients

  • Factor Xa Inhibitor
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]])
    • Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]])
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]])
  • Low-Dose Unfractionated Heparin (see Heparin, [[Heparin]])
  • Low Molecular Weight Heparin
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]])
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])
  • Sequential Compression Device (SCD) (see Sequential Compression Device, [[Sequential Compression Device]])
    • SCD’s Have Not Been Rigorously Evaluated in Critically Ill Patient Populations (Ann Surg, 2010) [MEDLINE]

Clinical Efficacy

  • Economic Evaluation of Pharmacologic DVT Prophylaxis vs Weekly Ultrasound Screening in ICU Patients (Am J Resp Crit Care Med, 2011) [MEDLINE]
    • Study: Markov decision analysis comparing weekly ultrasound screening (case finding) to pharmacologic prophylaxis in Canada/US/Australia
      • Limitations: there are no randomized trials examining screening for DVT in critically ill patients
    • Main Findings
      • In ICU patients who receive standard DVT prevention strategies, weekly Doppler compression ultrasound screening cost >$200k/QALY -> not cost-effective (note: interventions that cost >50-$100k/QALY are generally considered to not be cost-effective)
        • Although increased detection of DVT and PE was noted, screening was associated with more bleeding events (due to a greater frequency of anticoagulation and higher number of false-positive studies for DVT)
        • Very small improvements in quality-adjusted survival did not justify the additional costs of routine weekly screening
      • Appropriate pharmacologic prophylaxis combined with DVT case finding was at least as effective, less time-consuming, and less expensive than rotutine weekly ultrasound screening
      • This agrees with a prior study that failed to show benefit of routine ultrasound screening for DVT in critically ill patients [MEDLINE]
        • This study did find that weekly screening ultrasound was effective in the subset with femoral venous catheters
      • However, when risk of proximal DVT during critical illness was at least 16%, ultrasound screening cost <$50k/QALY and might be cost-effective
        • In patients with multiple trauma, acute brain or spinal cord injury, cancer, and in critically ill patients who do not receive pharmacologic prophylaxis, the risk of DVT may approach the 16% level [MEDLINE]
        • In a study of critically injured trauma patients who did not receive pharmacologic prophylaxis, the risk of proximal DVT was 18% [MEDLINE]
    • Conclusions: in ICU patients, efforts should be directed toward maximizing pharmacologic DVT prophylaxis, when possible
      • However, in select high-risk patient populations (as noted above), weekly screening ultrasound may be cost-effective
  • LIFENOX Trial (NEJM, 2011) [MEDLINE]: RCT (n = 8307) of enoxaparin with elastic stockings with graduated compression stockings vs elastic stockings with graduated compression stockings alone
    • Enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with decreased all-cause mortality rate in hospitalized, acutely ill medical patients
  • PROTECT Trial (NEJM, 2011) [MEDLINE]: comparative trial of dalteparin vs unfractionated heparin DVT prophylaxis (n = 1873)
    • Dalteparin was not superior to unfractionated heparin DVT prophylaxis, in terms of incidence of proximal DVT
  • Economic Evaluation Data Derived from PROTECT Trial (JAMA, 2014) [MEDLINE]: economic evaluation of dalteparin vs unfractionated heparin prophylaxis in medical and surgical critically ill patients (n = 2344 in 23 centers in 5 countries)
    • In critically ill medical-surgical patients undergoing pharmacologic DVT prophylaxis, dalteparin had lower PE rate, lower heparin-induced thromobcytopenia (HIT) rate, and similar or lower cost, as compared to unfractionated heparin DVT prophylaxis

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Asymptomatic Hypercoagulable State
    • Mechanical/Pharmacologic Prophylaxis is Not Recommended (Grade 1C Recommendation)
  • Chronically Immobilized Patients
    • Pharmacologic Prophylaxis is Not Recommended (Grade 2C Recommendation)
  • Critically Ill Patients
    • For Critically Ill Patients Routine Ultrasound Screening for Deep Venous Thrombosis is Not Recommended (Grade 2B Recommendation)
    • Low Molecular Weight Heparin or Low Dose Unfractionated Heparin Prophylaxis is Recommended (Grade 2C Recommendation)
    • For Critically Ill Patients with High Risk for Major Hemorrhage, Graduated Compression Stockings/Sequential Compression Devices are Recommended Until Bleeding Risk Decreases (at Which Time Pharmacologic Prophylaxis Should Be Substituted for Mechanical Prophylaxis) (Grade 2C Recommendation)
  • Hospitalized Acutely Ill Medical Patients
    • Hospitalized Acutely Ill Medical Patients with High Risk of Thrombosis, Low Molecular Weight Heparin, Low Dose Unfractionated Heparin Prophylaxis BID/TID, or Fondaparinux is Recommended (Grade 1B Recommendation)
    • For Hospitalized Acutely Ill Medical Patients with High Risk of Thrombosis and High Risk for Major Hemorrhage, Graduated Compression Stockings/Sequential Compression Devices are Recommended Until Bleeding Risk Decreases (at Which Time Pharmacologic Prophylaxis Should Be Substituted for Mechanical Prophylaxis) (Grade 2C Recommendation)
    • Hospitalized Acutely Ill Medical Patients with Low Risk of Thrombosis, No Pharmacologic or Mechanical Prophylaxis is Recommended
    • For Hospitalized Acutely Ill Medical Patients Who Receive an Initial Course of Prophylaxis, Extension of Duration Beyond the Period of Patient Immobilization or the Acute Hospital Stay is Not Recommended (Grade 2B Recommendation)
  • Persons Traveling Long Distance with Increased Risk of Venous Thrombembolism (Active Malignancy, Advanced Age, Estrogen Use, Known Hypercoagulable State, Limited Mobility, Pregnancy, Previous Venous Thromboembolism, Recent Surgery/Trauma, Severe Obesity)
    • Graduated Venous Compression Stockings (with 15-30 mm Hg of Pressure at the Ankle) are Recommended (Grade 2C Recommendation)

Abdominal-Pelvic Surgery Patients

Clinical Efficacy

  • Systematic Review of Risk of Heparin-Induced Thrombocytopenia in Post-Operative Patients Comparing Unfractionated Heparin vs Low Molecular Weight Heparin DVT Prophlaxis (Cochrane Database Syst Rev, 2012) [MEDLINE]
    • Lower incidence of HIT and HIT complicated by venous thromboembolism in post-operative patients undergoing low molecular weight heparin DVT prophylaxis compared with unfractionated heparin DVT prophylaxis
  • Economic Evaluation Data Derived from PROTECT Trial (JAMA, 2014) [MEDLINE]: economic evaluation of dalteparin vs unfractionated heparin prophylaxis in medical and surgical critically ill patients (n = 2344 in 23 centers in 5 countries)
    • In critically ill medical-surgical patients undergoing pharmacologic DVT prophylaxis, dalteparin had lower PE rate, lower heparin-induced thromobcytopenia (HIT) rate, and similar or lower cost, as compared to unfractionated heparin DVT prophylaxis

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Low Risk General/Abdominal-Pelvic Surgery (Approximately 1.5%; Rogers Score: 7-10; Caprini Score: 1-2): mechanical prophylaxis (preferably sequential compression devices) is recommended (Grade 2C Recommendation)
  • Moderate Risk General/Abdominal-Pelvic Surgery (Approximately 3.0%; Rogers Score: >10; Caprini Score: 3-4) without High Risk for Major Bleeding: low molecular weight heparin (Grade 2B Recommendation), low dose unfractionated heparin (Grade 2B Recommendation), or mechanical prophylaxis (preferably sequential compression devices) (Grade 2C Recommendation) are recommended
  • Moderate Risk General/Abdominal-Pelvic Surgery (Approximately 3.0%; Rogers Score: >10; Caprini Score: 3-4) with High Risk for Major Bleeding: mechanical prophylaxis (preferably sequential compression devices) is recommended (Grade 2C Recommendation)
  • High Risk General/Abdominal-Pelvic Surgery (Approximately 6.0%; Caprini Score: At Least 5) without High Risk for Major Bleeding: low molecular weight heparin (Grade 1B Recommendation) or low dose unfractionated heparin (Grade 1B Recommendation), AND mechanical prophylaxis (preferably sequential compression devices)
  • High Risk General/Abdominal-Pelvic Surgery (Approximately 6.0%; Caprini Score: At Least 5) with High Risk for Major Bleeding: mechanical prophylaxis (preferably sequential compression devices) is recommended (Grade 2C Recommendation)

Cardiac Surgery Patients

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Cardiac Surgery with Uncomplicated Post-Operative Course: mechanical prophylaxis (preferably sequential compression devices) is recommended (Grade 2C Recommendation)
  • Cardiac Surgery with Hospital Course Complicated by One or More Non-Hemorrhagic Surgical Complications: mechanical prophylaxis (preferably sequential compression devices) AND either low-dose unfractionated heparin or low molecular weight heparin prophylaxis is recommended (Grade 2C Recommendation)

Thoracic Surgery Patients

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Thoracic Surgery with Moderate Risk of Venous Thromboembolism (Without Risk for Post-Operative Hemorrhage): sequential compression devices (Grade 2C Recommendation), low-dose unfractionated heparin (Grade 2B Recommendation), or low molecular weight heparin prophylaxis (Grade 2B Recommendation) is recommended

Craniotomy Patients

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Craniotomy: mechanical prophylaxis (preferably sequential compression devices) is recommended (Grade 2C Recommendation)
  • Craniotomy with Very High Risk for Venous Thromboembolism (Craniotomy Performed for Malignant Disease): mechanical prophylaxis (preferably sequential compression devices) is recommended with addition of pharmacologic prophylaxis once hemostasis is established and the risk of bleeding decreases (Grade 2C Recommendation)

Spinal Surgery Patients

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Spinal Surgery: sequential compression devices (Grade 2C Recommendation), low-dose unfractionated heparin (Grade 2C Recommendation), or low molecular weight heparin prophylaxis (Grade 2C Recommendation) is recommended
  • Spinal Surgery with Very High Risk for Venous Thromboembolism (Spinal Surgery Performed for Malignant Disease or Surgery with Combined Anterior-Posterior Approach): mechanical prophylaxis (preferably sequential compression devices) is recommended with addition of pharmacologic prophylaxis once hemostasis is established and the risk of bleeding decreases (Grade 2C Recommendation)

Major Trauma Patients (Traumatic Brain Injury, Traumatic Spinal Injury, Spine Surgery for Trauma)

Clinical Efficacy

  • Cost-Effectiveness Retrospective Analysis of DVT Surveillance in Trauma Patients (n = 4234) in the ICU (PLoS One, 2014) [MEDLINE]
    • Ultrasound Screening of Trauma Patients is Cost-Effective: cost is $29,102/QALY

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Major Trauma: sequential compression devices (Grade 2C Recommendation), low-dose unfractionated heparin (Grade 2C Recommendation), or low molecular weight heparin prophylaxis (Grade 2C Recommendation) is recommended
  • Major Trauma with Very High Risk for Venous Thromboembolism: mechanical prophylaxis (preferably sequential compression devices) should be added to pharmacologic prophylaxis if not contraindicated by lower extremity injury (Grade 2C Recommendation)
  • Major Trauma with Contraindications to Low-Dose Unfractionated Heparin/Low Molecular Weight Heparin: mechanical prophylaxis (preferably sequential compression devices) is recommended (when not contraindicated by presence of lower extremity injury) (Grade 2C Recommendation), with addition of low-dose unfractionated heparin/low molecular weight heparin when bleeding risk decreases or contraindication heparin resolves (Grade 2C)
  • IVC Filter Placement as Primary Prevention of Venous Thromboembolism in Major Trauma: not recommended (Grade 2C Recommendation)
  • Screening Lower Extremity Doppler Ultrasound in Major Trauma: not recommended (Grade 2C Recommendation)

Orthopedic Surgery Patients (Total Hip Arthroplasty, Total Knee Arthroplasty, Hip Fracture Surgery)

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Type of DVT Prophylaxis for Total Hip Arthroplasty/Total Knee Arthroplasty: one of the following is recommended for a minimum of 10-14 days
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]]) (Grade 1B Recommendation)
    • Aspirin (see Acetylsalicylic Acid, [[Acetylsalicylic Acid]]) (Grade 1B Recommendation)
    • Coumadin (see Coumadin, [[Coumadin]]) (Grade 1B Recommendation)
    • Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]) (Grade 1B Recommendation)
    • Low Molecular Weight Heparin (Grade 1B Recommendation): low molecular weight heparin (if started pre-operatively, started 12 hrs before surgery) is suggested as the preferred agent for DVT prophylaxis (in terms of bleeding risk, efficacy, and long-term safety data) for total hip arthroplasty/total knee arthroplasty (Grade 2C Recommendation vs apixaban/dabigatran/fondaparinux/low-dose unfractionated heparin/rivaroxaban; Grade 2C Recommendation vs aspirin/coumadin)
      • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]])
      • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
      • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])
    • Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]]) (Grade 1B Recommendation)
    • Low-Dose Unfractionated Heparin Prophylaxis (see Heparin, [[Heparin]]) (Grade 1B Recommendation)
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]]) (Grade 1B Recommendation)
    • Sequential Compression Device (SCD) (see Sequential Compression Device, [[Sequential Compression Device]]) (Grade 1C Recommendation): suggested to be used alone if bleeding risk contraindicates use of an antithrombotic agent (Grade 2C Recommendation)
  • Type of DVT Prophylaxis Hip Fracture Surgery: one of the following is recommended for 10-14 days
    • Aspirin (see Acetylsalicylic Acid, [[Acetylsalicylic Acid]]) (Grade 1B Recommendation)
    • Coumadin (see Coumadin, [[Coumadin]]) (Grade 1B Recommendation)
    • Low Molecular Weight Heparin (Grade 1B Recommendation): low molecular weight heparin (if started pre-operatively, started at least 12 hrs before surgery) is suggested as the preferred agent for DVT prophylaxis (in terms of bleeding risk, efficacy, and long-term safety data) for hip fracture surgery (Grade 2C Recommendation vs fondaparinux/low-dose unfractionated heparin; Grade 2C Recommendation vs aspirin/coumadin)
      • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]])
      • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
      • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])
    • Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]]) (Grade 1B Recommendation)
    • Low-Dose Unfractionated Heparin Prophylaxis (see Heparin, [[Heparin]]) (Grade 1B Recommendation)
    • Sequential Compression Device (SCD) (see Sequential Compression Device, [[Sequential Compression Device]]) (Grade 1C Recommendation): suggested to be used alone if bleeding risk contraindicates use of an antithrombotic agent (Grade 2C Recommendation)
  • Dual DVT Prophylaxis with Antithrombotic Agent and Sequential Compression Device for Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery During the Hospital Stay: recommended (Grade 2C Recommendation)
  • Timing of Initiation of DVT Prophylaxis for Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery: starting DVT prophylaxis at least 12 hrs pre-operatively or 12 or more hrs post-operatively is recommended (Grade 1B Recommendation)
  • Duration of DVT Prophylaxis for Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery: duration of prophylaxis in the outpatient period for up to 35 days from the date of surgery is suggested (Grade 2B Recommendation)
  • IVC Filter Placement as Primary Prevention of Venous Thromboembolism in Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery: not recommended (Grade 2C Recommendation)
  • Screening Lower Extremity Doppler Ultrasound in Asymptomatic Total Hip Arthroplasty/Total Knee Arthroplasty and Hip Fracture Surgery Prior to Hospital Discharge: not recommended (Grade 1B Recommendation)

Isolated Lower Leg Injury (Distal to Knee) Patients

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Isolated Lower Leg Injury Requiring Immobilization: no prophylaxis is recommended (Grade 2C Recommendation)

Knee Arthroscopy Patients

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

  • Knee Arthroscopy without Prior History of Venous Thromboembolism: no prophylaxis is recommended (Grade 2B Recommendation)

Treatment

Strength of Clinical Indication for Anticoagulation in Lower Extremity Proximal vs Distal Deep Venous Thrombosis

  • Comparative Risks of Pulmonary Embolism: the risk of pulmonary embolism is higher with proximal lower extremity DVT than with distal lower extremity DVT
    • Over 90% of pulmonary emboli arise from proximal lower extremity veins (Lancet, 1974) [MEDLINE] (Acta Chir Scand Suppl, 1977) [MEDLINE]
    • Comparative Mortality Rates (Data from OPTIMEV Study): the mortality rate of proximal lower extremity DVT is higher (8%) than the mortality rate of distal lower extremity DVT (4.4%) (Thromb Haemost, 2009) [MEDLINE]

General Goals of Anticoagulation

  • Prevention of Early Complications of Venous Thromboembolism: the benefits of anticoagulation are greatest during the initial period of anticoagulation
    • Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])
    • Clot Extension: anticoagulation inhibits clot extension
    • Death: anticoagulation decreases risk of DVT recurrence and mortality rate [MEDLINE]
  • Prevention of Late Complications of Venous Thromboembolism
    • Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (see Chronic Thromboembolic Pulmonary Hypertension, [[Chronic Thromboembolic Pulmonary Hypertension]])
    • Recurrent Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
      • Anticoagulation decreases risk of DVT recurrence and mortality rate [MEDLINE]
      • Anticoagulation decreases the risk of recurrence venous thromboembolism to 3.4% and risk of fatal venous thromboembolism to 0.4% [MEDLINE]
    • Post-Thrombotic (Post-Phlebitic) Syndrome (see Post-Thrombotic Syndrome, [[Post-Thrombotic Syndrome]])

Initial Treatment of Venous Thrombembolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Requirements for Parenteral Anticoagulation with Specific Long-Term Anticoagulants

  • Parenteral Anticoagulation is Indicated Prior to Coumadin
    • Conversion from Parenteral Anticoagulation to Coumadin
      • Coumadin Should Be Started Concurrently with Parenteral Anticoagulation, Rather Than Waiting (Grade 2C Recommendation) [MEDLINE]: start coumadin 5 mg qday (with a lower dose used in elderly or those with a high risk of bleeding, malnutrition, debility, congestive heart failure, or liver disease)
      • Coumadin Should Be Overlapped with Parenteral Anticoagulation for at Least 4-5 Days
      • Parenteral Anticoagulation Can Be Discontinued When INR Remains >2 for at Least 2 Consecutive Days
  • Parenteral Anticoagulation is Indicated Prior to Dabigatran (Pradaxa)
    • Conversion from Unfractionated Heparin Drip/Argatroban Drip to Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): start dabigatran as soon as drip is stopped
    • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) or Fondaparinux to Dabigatran (Dabigatran) (see Dabigatran, [[Dabigatran]]): start dabigatran approximately 2 hrs prior to next scheduled dose of subcutaneous agent
  • Parenteral Anticoagulation is Indicated Prior to Edoxaban (Savaysa, Lixiana)
    • Conversion from Unfractionated Heparin/Argatroban Drip to Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): discontinue heparin/argatroban drip and initiate edoxaban 4 hrs later
    • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) to Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): discontinue low molecular weight heparin and initiate edoxaban at the time of the next scheduled administration of low molecular weight heparin
  • Parenteral Anticoagulation is Not Indicated Prior to Apixaban (Eliquis)/Rivaroxaban (Xarelto) (see Apixaban, [[Apixaban]] and Rivaroxaban, [[Rivaroxaban]])

Parenteral Anticoagulants

  • Argatroban (Acova) (see Argatroban, [[Argatroban]])
  • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C Recommendation
  • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
  • Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]])
  • Unfractionated Heparin (see Heparin, [[Heparin]])
  • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])

Risk Stratification for Anticoagulation-Associated Hemorrhage

  • Risk Factors for Anticoagulation-Associated Hemorrhage
  • Absolute Risk of Major Hemorrhage
    • Anticoagulation Duration: 0-3 mo
      • Low Risk (0 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.6%
        • Increased Risk of Hemorrhage = 1.0%
        • Total Risk of Hemorrhage = 1.6%
      • Moderate Risk (1 Risk Factors)
        • Baseline Risk of Hemorrhage = 1.2%
        • Increased Risk of Hemorrhage = 2.0%
        • Total Risk of Hemorrhage = 3.2%
      • High Risk (At Least 2 Risk Factors)
        • Baseline Risk of Hemorrhage = 4.8%
        • Increased Risk of Hemorrhage = 8.0%
        • Total Risk of Hemorrhage = 12.8%
    • Anticoagulation Duration: After First 3 mo
      • Low Risk (0 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.3%/year
        • Increased Risk of Hemorrhage = 0.5%/year
        • Total Risk of Hemorrhage = 0.8%/year
      • Moderate Risk (1 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.6%/year
        • Increased Risk of Hemorrhage = 1.0%/year
        • Total Risk of Hemorrhage = 1.6%/year
      • High Risk (At Least 2 Risk Factors)
        • Baseline Risk of Hemorrhage = at least 2.5%/year
        • Increased Risk of Hemorrhage = at least 4.0%/year
        • Total Risk of Hemorrhage = at least 6.5%/year

Long-Term Treatment of Venous Thromboembolism without Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • First-Line Agents
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]]): Grade 2B Recommendation
    • Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): Grade 2B Recommendation
    • Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): Grade 2B Recommendation
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]]): Grade 2B Recommendation
  • Second-Line Agents
    • Coumadin (see Coumadin, [[Coumadin]]): Grade 2C Recommendation
      • Recommended INR Range: 2-3 (Grade 1B Recommendation) [MEDLINE]
  • Third-Line Agents: Low Molecular Weight Heparins
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C Recommendation
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]]): Grade 2C Recommendation
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]]): Grade 2C Recommendation

Long-Term Treatment of Venous Thromboembolism with Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • First-Line Agents: Low Molecular Weight Heparins
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C Recommendation
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]]): Grade 2C Recommendation
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]]): Grade 2C Recommendation
  • Second-Line Agents
    • Coumadin (see Coumadin, [[Coumadin]]): Grade 2C Recommendation
      • Recommended INR Range: 2-3 (Grade 1B Recommendation) [MEDLINE]
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]]): Grade 2C Recommendation
    • Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): Grade 2C Recommendation
    • Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): Grade 2C Recommendation
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]])): Grade 2C Recommendation

Specific Duration of Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Proximal DVT/Acute PE, Provoked by Surgery: 3 months (Grade 1B Recommendation)
  • Proximal DVT/Acute PE, Provoked by Non-Surgical Transient Risk Factor: 3 months (Grade 1B Recommendation)
  • Distal DVT, Unprovoked: 3 months (Grade 1B recommendation), assuming that anticoagulation is desired by the patient
  • Distal DVT, Provoked by Surgery or by a Non-Surgical Transient Risk Factor: 3 months (Grade 2C recommendation), assuming that anticoagulation is desired by the patient
  • First Unprovoked Proximal DVT/Acute PE
    • Low/Moderate Bleeding Risk (See Risk Factors for Hemorrhage Above): indefinite anticoagulation (Grade 2B Recommendation)
    • High Bleeding Risk (See Risk Factors Above): 3 months (Grade 1B Recommendation)
  • Second Unprovoked Proximal DVT/Acute PE
    • Low Bleeding Risk: indefinite anticoagulation (Grade 1B Recommendation)
    • Moderate Bleeding Risk: indefinite anticoagulation (Grade 2B Recommendation)
    • High Bleeding Risk: 3 months (Grade 2B Recommendation)
  • Proximal DVT/Acute PE with Cancer
    • Low/Moderate Bleeding Risk: indefinite anticoagulation (Grade 1B Recommendation)
    • High Bleeding Risk: indefinite anticoagulation (Grade 2B Recommendation)

Specific Clinical Features Which May Influence the Choice of Specific Initial/Long-Term Anticoagulants (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Cancer: preferred anticoagulant(s) -> low molecular weight heparin
  • Parenteral Therapy is to Be Avoided: preferred anticoagulant(s) -> apixaban, rivaroxaban
    • Coumadin, dabigatran, and edoxaban require initial parenteral anticoagulant therapy
  • Once Daily PO Therapy is Preferred: preferred anticoagulant(s) -> edoxaban, rivaroxaban, coumadin
  • Liver Disease/Coagulopathy: preferred anticoagulant(s) -> low molecular weight heparin
    • Novel oral anticoagulants are contraindicated if INR is elevated due to liver disease
    • Coumadin is difficult to control and INR may not reflect anti-thrombotic effect in liver disease
  • Chronic Kidney Disease (CrCl <30 mL/min): preferred anticoagulant(s) -> coumadin
    • Novel oral anticoagulants and low molecular weight heparins are contraindicated with severe renal insufficiency
    • Dosing of novel oral anticoagulants are variable, dependent on the agent
    • Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (2016) [MEDLINE]
      • CrCl 50-80 mL/min: novel oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
      • CrCl <50 mL/min: novel oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
      • Apixaban had the lowest rate of major bleeding in this subgroup (see Apixaban, [[Apixaban]])
  • Coronary Artery Disease (CAD): preferred anticoagulant(s) -> coumadin, apixaban, edoxaban, rivaroxaban
    • Coronary artery events occur more frequently with dabigatran than with coumadin: this is not seen with other novel oral anticoagulants
    • If possible, antiplatelet therapy (for coronary artery disease) should be avoided in patients on anticoagulants because of increased bleeding
  • Dyspepsia/Gastrointestinal Hemorrhage: preferred anticoagulant(s) -> coumadin, apixaban
    • Dabigatran increases dyspepsia
    • Dabigatran, rivaroxaban, and edoxaban may be associated with more gastrointestinal hemorrhage than coumadin
  • Poor Compliance: preferred anticoagulant(s) -> coumadin
    • INR monitoring can help to detect compliance problems
  • Thrombolytic Therapy Use: preferred anticoagulant(s) -> unfractionated heparin drip
    • There is a greater level of experience with unfractionated heparin use in patients treated with thrombolytic therapy
  • Reversal Agent Required: preferred anticoagulant(s) -> coumadin, unfractionated heparin drip, dabigatran
  • Pregnancy: preferred anticoagulant(s) -> low molecular weight heparin
    • There is a Potential for Other Agents to Cross the Placenta in Pregnancy
      • Coumadin is known to be teratogenic
  • Cost/Coverage Issues: preferred anticoagulant(s) -> variable
    • Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (2014): rivaroxaban cost $2,448 per-patient less and was associated with 0.0058 more QALY’s compared with enoxaparin + coumadin
    • Cost-Effectiveness of Novel Oral Anticoagulants, Compared to Coumadin, in Non-Valvular Atrial Fibrillation and Venous Thromboembolism (2015) [MEDLINE]: medical costs are reduced when novel oral anticoagulants are used instead of coumadin for the treatment of non-valvular atrial fibrillation/venous thromboembolism, with apixaban being associated with the greatest reduction in medical costs
    • UK Study of Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (2015) [MEDLINE]: rivaroxaban was a cost-effective choice for acute treatment of venous thromboembolism and secondary prevention of venous thromboembolism, compared with low molecular weight heparin/coumadin treatment, regardless of treatment duration

ANTICOAG PREF

Specific Treatment of Acute Pulmonary Embolism with Hypotension (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale
    • Systemic Thrombolytic Therapy Accelerates Resolution of Pulmonary Embolism (with More Rapid Lowering of Pulmonary Artery Pressure, Improved Hypoxemia, and Resolution of Perfusion Scan Defects): however, systemic thrombolytic therapy also increases the risk of hemorrhage
    • Catheter-Directed Thrombolysis Uses Approximately 33% of the Dose of Thrombolytic That Systemic Thrombolysis Uses: effectively lowering bleeding risk
      • Catheter-Directed Thrombolysis Achieves Higher Local Concentrations of Thrombolytics at the Site of the PE and Also Facilitates Thrombus Fragmentation and Permeability Via the Catheter
  • Agents
    • Alteplase (Activase) (see Alteplase, [[Alteplase]])
  • Major Contraindications to Systemic Thrombolytic Therapy
    • Active Bleeding
    • Bleeding Diathesis
    • Diabetic Retinopathy
    • History of Intracranial Hemorrhage
    • History of Ischemic CVA <3 mo Ago
    • Recent Brain/Spinal Surgery
    • Recent Head Trauma with Fracture/Traumatic Brain Injury
    • Structural Intracranial Disease
  • Relative Contraindications to Systemic Thrombolytic Therapy
    • Age >75 y/o
    • Anticoagulation: coumadin, etc
    • Black Race
    • Diastolic BP >110
    • Female Sex
    • History of Ischemic CVA >3 mo Ago
    • Low Body Weight
    • Pericarditis/Pericardial Effusion
    • Pregnancy
    • Recent Invasive Procedure
    • Recent Non-Intracranial Hemorrhage
    • Recent Surgery
    • Systolic BP >180
    • Traumatic Cardiopulmonary Resuscitation
  • Clinical Efficacy
    • Meta-Analysis of Thrombolyis in Acute PE (2014) [MEDLINE]: meta-analysis (16 trials, n = 2115)
      • Thrombolysis decreased mortality rate (2.17%), as compared to anticoagulation alone (3.89%)
        • No mortality benefit was observed in patients >65 y/o, a population in whom the risk of hemorrhage was greatest
      • Thrombolysis decreased the risk of recurrent PE (1.17%) as compared to anticoagulation alone (3.04%)
      • Thrombolysis increased the risk of major hemorrhage (9.2%), as compared to anticoagulation alone (3.4%)
        • No significant difference in major hemorrhage in patients 65 y/o and younger
      • Thrombolysis increased the risk of intracranial hemorrhage (1.5%), as compared to anticoagulation alone (0.2%)
    • PEITHO Trial (2014) [MEDLINE]: RCT of tenecteplase (n = 1006), intention-to-treat analysis in normotensive, intermediate-risk PE patients
      • Thrombolysis decreased hemodynamic decompensation (2.6%), as compared to placebo group (5.6%)
      • No difference in 30-day mortality rate
      • Thrombolysis increased risk of major hemorrhage and stroke
  • Recommendations
    • Systemic Thrombolytics are Indicated for Acute PE with Hypotension (Grade 2B Recommendation)
    • Systemic Thrombolytic Therapy is Recommended Over Catheter-Directed Thrombolysis for Acute PE with Hypotension (Grade 2C Recommendation): however, the bleeding risk may indicate catheter-directed thrombolysis in centers where local expertise is present
    • Systemic Thrombolytic Therapy Can Also Be Considered in Patient Who Deteriorates After Starting Anticoagulation (Significant Hypoxemia, Poor Tissue Perfusion, etc), But Who Has Not Developed Hypotension Yet

Specific Treatment of Acute Subsegmental Pulmonary Embolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Rationale/Background

  • Improvements in CT Angiography Have Led Increased Diagnosis of Subsegmental PE’s: subsegmental PE’s have increased from approximately 5% to more than 10% of all detected PE’s
  • Due to Small Size of Subsegmental PE’s, They are More Likely to Be a False-Positive Finding than a PE in the Segmental/More Proximal Pulmonary Arteries
    • Subsgmental PE is more likely to be a real finding if the CT pulmonary angiogram is of high quality with good opacification of the distal pulmonary arteries, there are multiple intraluminal defects, defects involve more proximal (larger) subsegmental arteries, defects are seen on more than one image, defects are surrounded by contrast rather than adherent to pulmonary artery walls, defects are seen on more than one projection, patient is symptomatic (as opposed to PE being an incidental finding), there is a high clinical pretest probability for PE, and/or D-dimer level is elevated without other explanation
  • Since a True Subsegmental PE is Likely to Have Arisen From a Small DVT, the Risk of Progressive or Recurrent VTE Without Anticoagulation is Expected to Be Lower Than in Patients with a Larger PE

Recommendations

  • Subsegmental Acute Pulmonary Embolism + No Proximal DVT + Low Risk of Recurrent Venous Thrombembolism: clinical surveillance (with serial LE Dopplers, etc) is recommended over anticoagulation (Grade 2C Recommendation)
    • Factors Associated with Low Risk of Recurrent Venous Thromboembolism
      • Absence of Active Cancer
      • Normal Mobility
      • Outpatient Status
      • Presence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
    • Presence of High Risk of Bleeding May Favor Clinical Surveillance Strategy Over Anticoagulation
  • Subsegmental Acute Pulmonary Embolism + No Proximal DVT + High Risk of Recurrent Venous Thrombembolism: anticoagulation is recommended over clinical surveillance (Grade 2C Recommendation)
    • Factors Associated with High Risk of Recurrent Venous Thromboembolism
      • Active Cancer (Especially if Metastatic or on Chemotherapy)
      • Decreased Mobility
      • Hospitalization
      • Absence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
    • Presence of Low Cardiopulmonary Reserve May Favor Anticoagulation Over Surveillance Strategy

Specific Treatment of Low-Risk Acute Pulmonary Embolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Criteria for Outpatient Treatment of Acute PE (or Early Discharge to Home)
    • Clinically Stable with Good Cardiopulmonary Reserve
    • No Specific Contraindications, Such as Recent Bleeding, Severe Renal Disease, Severe Liver Disease, or Severe Thrombocytopenia (Platelets <70k)
    • Patient is Expected to be Compliant with Treatment
    • Patient Feels Well Enough to be Treated at Home
  • Other Criteria-Pulmonary Embolism Severity Index (PESI): score <85
  • Other Criteria-Simplified Pulmonary Embolism Severity Index (Simplified PESI): score 0
  • Other Factors Which Might Merit Inpatient Treatment Instead of Outpatient Treatment
    • Increased Cardiac Biomarker Levels
    • Presence of Right Ventricular Dysfunction
  • Recommendations
    • Low Risk PE Patients May Be Treated at Home or Discharged Early (Such as After the First 5 Days of Treatment)

Specific Treatment of Recurrent Venous Thromboembolism While on Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale
    • Risk of Recurrent Venous Thromboembolism Decreases Rapidly After Starting Anticoagulation: based on this, a recurrence soon after therapy can generally be managed by increasing the intensity of anticoagulation
  • Risk Factors for Recurrent Venous Thromboembolism
  • Recommendations
    • Treatment of Recurrent Venous Thromboembolism on a Non-Low Molecular Weight Heparin (Coumadin or Oral Agent): switch to low molecular weight heparin is recommended, at least temporarily (Grade 2C Recommendation)
    • Treatment of Recurrent Venous Thromboembolism on a Low Molecular Weight Heparin: higher dose of low molecular weight heparin (by 25-33%) is recommended (Grade 2C Recommendation)

Specific Use of Aspirin for Extended Treatment of Venous Thromboembolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Unprovoked Proximal DVT/Acute PE: when anticoagulation is stopped, aspirin is recommended (if there is no contraindication) to decrease recurrence risk of venous thromboembolism (Grade 2B Recommendation)
    • Note: aspirin is far less effective than anticoagulation and is therefore, not a substitute for anticoagulation

Inferior Vena Cava (IVC) Filter Placement (see Inferior Vena Cava Filter, [[Inferior Vena Cava Filter]])

  • Historical Perspective: IVC filter use in the management of venous thromboembolism has increased over the last few decades [MEDLINE] [MEDLINE]
  • Indications for Inferior Vena Cava Filter
    • Absolute Contraindication to Anticoagulation
      • Active Hemorrhage
      • Fall Risk: particularly in older patient
      • History of Intracranial Hemorrhage
      • Major Trauma
      • Recent or Planned Emergency Surgery/Procedure
      • Severe Coagulopathy (see Coagulopathy, [[Coagulopathy]])
      • Severe or Uncontrolled Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
      • Severe Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): platelet count <50k
      • Unstable Aortic Dissection (see Aortic Dissection, [[Aortic Dissection]])
    • Relative Contraindication to Anticoagulation
      • Intracranial/Spinal Tumor
      • Large Abdominal Aortic Aneurysm with Severe Hypertension (see Abdominal Aortic Aneurysm, [[Abdominal Aortic Aneurysm]])
      • Mild or Controlled Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
      • Mild-Moderate Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): platelet count <150k
      • Stable Aortic Dissection (see Aortic Dissection, [[Aortic Dissection]])
    • Complication of Anticoagulation
      • Anticoagulation Failure: objectively documented extension of existing DVT (or new DVT) or PE while therapeutically anticoagulated
      • Coumadin Skin Necrosis (see Coumadin, [[Coumadin]])
      • Drug Reaction
      • Hemorrhage (Major or Minor)
      • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
      • Poor Compliance with Anticoagulation Regimen
    • Failure of Previous Device to Prevent Pulmonary Embolism: central extension of thrombus through an existing filter or recurrent PE
    • In Association with Thrombectomy, Embolectomy, or Lytic Therapy
    • Prophylaxis with No Thromboembolic Disease
    • Prophylaxis with Thromboembolism in Addition to Anticoagulation
  • Technique
    • Filter Positioning: IVC filters are typically placed infrarenally, since suprarenal filters may lead to renal vein compromise, if they become clotted
    • Retrievable Inferior Vena Cava Filters: may remain in place for approximately 2 mo
    • There is No Data to Support One IVC Filter Brand Over Another
  • Clinical Efficacy
    • Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group (PREPIC) Trial (NEJM, 1998) [MEDLINE]
      • At 2 years, IVC filter had no impact on the rate of symptomatic PE or mortality rate
      • However, IVC filter placement increased the rate of recurrent DVT
    • Randomized, Open-Label PREPIC2 Trial of IVC Filter Added to Anticoagulation in Severe Acute PE Requiring Hospitalization (JAMA, 2015) [MEDLINE]: retrievable IVC filter had no clinical benefit over anticoagulation alone (in terms of decreasing the risk of recurrent PE at 3/6 months or 3-month/6-month mortality rate)
      • Based on these data, IVC filter is not indicated in anticoagulated acute PE patients on the basis of poor cardiopulmonary reserve, large clot burden, or suspected risk of recurrence
    • Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines [MEDLINE]: for patients with venous thromboembolism treated with anticoagulation, IVC filter placement is not recommended

Specific Treatment of Lower Extremity Deep Venous Thrombosis

Ambulation

  • Ambulation is Indicated as Soon as Possible (Despite the Theoretical Risk for Embolization): usually a gradual increase in ambulation is advisable
    • Ambulation has not been shown to increase the risk of fatal pulmonary embolism

Graduated Compression Stockings (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale: may provide symtomatic relief and facilitate ambulation
    • Theoretical goal of therapy is the prevention of post-phlebitic syndrome (although data are conflicting as to their efficacy in this regard)
  • Contraindications
    • Allergy to the Stocking Material
    • Inability to Apply Stockings
    • Severe Arterial Insufficiency
    • Skin Ulceration
  • Recommendations
    • Graduated Compression Stockings are Not Recommended in Acute DVT to Prevent Post-Thrombotic Syndrome (Grade 2B Recommendation): however they may be used for patients with acute/chronic DVT symptoms

Catheter-Directed Thrombolysis of Acute Lower Extremity Deep Venous Thrombosis (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]]) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale
    • Retrospective Analysis of Catheter-Directed Thrombolysis for Lower Extremity DVT (JAMA Int Med, 2014) [MEDLINE]
      • Catheter-Directed Thrombolysis of Lower Extremity DVT is Associated with 2x-Increased Risk of Transfusion, 3x-Increased Risk of Intracranial Hemorrhage, 1.5x-Increased Risk of Acute PE, and 2x-Increased Risk of IVC Filter Insertion: long-term outcomes were not reported
  • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Lower Extremity DVT)
    • Failure of Anticoagulation
    • Good Functional Status
    • Iliofemoral DVT/Phlegmasia Cerulea Dolens
    • Life Expectancy of At Least 1 Year
    • Low Risk of Hemorrhage
    • Symptoms for <14 Days
  • Recommendations
    • Anticoagulation is Recommended Over Catheter-Directed Thrombolysis for Lower Extremity DVT (Grade 2C Recommendation)
      • Patients who put a high value on the prevention of post-thrombotic (post-phlebitic) syndrome and lower value on initial complexity, cost, and risk of bleeding may choose catheter-directed thrombolysis (see Post-Thrombotic Syndrome, [[Post-Thrombotic Syndrome]])

Treatment of Isolated Distal (Calf) Deep Venous Thrombosis (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale: approximately 15% of untreated distal DVT’s will ultimately extend proximally into the popliteal vein and may cause acute PE [MEDLINE]
  • Isolated Distal DVT without Severe Symptoms or Risk Factors for Extension: serial LE Dopplers x 2 wks are recommended (Grade 2C Recommendation)
    • During Surveillance
      • Thrombus Extends within the Distal Veins -> Anticoagulation is Suggested (Grade 2C Recommendation)
      • Thrombus Extends into the Proximal Veins -> Anticoagulation is Recommended (Grade 1B Recommendation)
  • Isolated Distal DVT with Severe Symptoms or Risk Factors for Extension: anticoagulation is recommended (Grade 2C Recommendation)
    • Risk Factors for Extension of Distal DVT
      • Active Cancer
      • Extensive Thrombosis: >5 cm in length, involving multiple veins, >7 mm in maximum diameter
      • History of Venous Thromboembolism
      • Inpatient Status
      • No Reversible Provoking Factor for DVT
      • Positive D-Dimer: particularly when markedly elevated without an alternative reason
      • Thrombosis Close to Proximal Veins: thrombosis confined to the muscular veins of the calf (soleus, gastrocnemius) has a lower risk of extension than thrombosis that involves the axial (true deep: peroneal, tibial) veins

Specific Treatment of Upper Extremity Deep Venous Thrombosis

General Treatment

  • Recommendations Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Anticoagulation is Recommended for Upper Extremity Deep Venous Thrombosis Involving the Axillary or More Proximal Veins

Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis Which Involves Axillary or More Proximal Veins (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Upper Extremity DVT)
    • Good Functional Status
    • Life Expectancy of at Least 1 Year
    • Low Risk of Hemorrhage
    • Severe Symptoms
    • Symptoms for <14 Days
    • Thrombus Involving Most of the Axillary and Subclavian Vein
  • Recommendations
    • Anticoagulation is Recommended Over Catheter-Directed Thrombolysis in Upper Extremity Deep Venous Thrombosis (Grade 2C Recommendation)
    • In Patients Who Undergo Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis, the Same Intensity/Duration of Anticoagulation is Recommended as in Those Who Do Not Undergo Thrombolysis (Grade 1B Recommendation)

References

General

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  • Source of non-lethal pulmonary emboli. Lancet. 1974 Feb 16;1(7851):258-9 [MEDLINE]
  • Deep vein thrombosis and pulmonary embolism. An autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand Suppl. 1977;478:1-120 [MEDLINE]
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  • A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331:1601–1606 [MEDLINE]
  • A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409 [MEDLINE]
  • Vena caval filters: a comprehensive review. Blood. 2000;95(12):3669 [MEDLINE]
  • Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000;343(24):1758 [MEDLINE]
  • Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358(9275):9 [MEDLINE]
  • Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med 2001;161:1268–1279 [MEDLINE]
  • Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163(14):1711 [MEDLINE]
  • Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005; 172:1041-1046 [MEDLINE]
  • Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med. 2005 Jul;33(7):1565-71 [MEDLINE]
  • Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172 [MEDLINE]
  • Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost. 2009 Sep;102(3):493-500. doi: 10.1160/TH09-01-0053 [MEDLINE]
  • RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170: 1383–1389 [MEDLINE]
  • Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010;137(5):1145 [MEDLINE]
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  • Reproducibility of CT signs of right ventricular dysfunction in acute pulmonary embolism. AJR Am J Roentgenol 2010; 194:1500-1506 [MEDLINE]
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  • Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010 May 4;152(9):578-89. doi: 10.7326/0003-4819-152-9-201005040-00008 [MEDLINE]
  • Deep vein thrombosis: a clinical review. J Blood Med. 2011; 2: 59–69 [MEDLINE]
  • Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171(9):831 [MEDLINE]
  • Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. BMJ. 2011 May 24;342:d3036. doi: 10.1136/bmj.d3036 [MEDLINE]
  • Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. doi: 10.1378/chest.1412S3 [MEDLINE]
  • Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med. 2012 May;125(5):478-84. Epub 2012 Feb 4 [MEDLINE]
  • Factors in the technical quality of gadolinium enhanced magnetic resonance angiography for pulmonary embolism in PIOPED III. Int J Cardiovasc Imaging. 2012 Feb;28(2):303-12. doi: 10.1007/s10554-011-9820-7. Epub 2011 Feb 24 [MEDLINE]
  • A meta-analysis of anticoagulation for calf deep venous thrombosis. J Vasc Surg. 2012 Jul;56(1):228-37.e1; discussion 236-7. doi: 10.1016/j.jvs.2011.09.087. Epub 2011 Dec 29 [MEDLINE]
  • Use of Glucocorticoids and Risk of Venous Thromboembolism: A Nationwide Population-Based Case-Control Study. JAMA Intern Med. 2013 Apr 1:1-1 [MEDLINE]
  • Acute pulmonary embolism: external validation of an integrated risk stratification model. Chest 2013 Jun 13. doi: 10.1378/chest.12-2938 [MEDLINE]
  • Identification of intermediate-risk patients with acute symptomatic pulmonary embolism. Eur Respir J. 2014 Sep;44(3):694-703. doi: 10.1183/09031936.00006114. Epub 2014 Apr 2 [MEDLINE]
  • Vena cava filters in unstable elderly patients with acute pulmonary embolism. Am J Med. 2014 Mar;127(3):222-5. Epub 2013 Nov 23 [MEDLINE]
  • Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology (Oxford). 2015 Apr;54(4):736-42. doi: 10.1093/rheumatology/keu408. Epub 2014 Sep 24 [MEDLINE]
  • Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care. BMJ. 2015;351:h4438 [MEDLINE]
  • Trends in incidence versus case fatality rates of pulmonary embolism: Good news or bad news? Thromb Haemost. 2016 Jan;115(2):233-5. Epub 2015 Dec 03 [MEDLINE]

DVT Prophylaxis

  • Cost-effectiveness of ultrasound in preventing femoral venous catheter-associated pulmonary embolism. Am J Respir Crit Care Med 2003;168:1481–1487 [MEDLINE]
  • Efficacy of deep venous thrombosis prophylaxis in the medical intensive care unit. J Intensive Care Med. 2006 Nov-Dec;21(6):352-8 [MEDLINE]
  • Intermittent pneumatic compression or graduated compression stockings for deep vein thrombosis prophylaxis? A systematic review of direct clinical comparisons. Ann Surg. 2010 Mar;251(3):393-6. doi: 10.1097/SLA.0b013e3181b5d61c [MEDLINE]
  • PROTECT Trial: Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011 Apr 7;364(14):1305-14. doi: 10.1056/NEJMoa1014475 [MEDLINE]
  • Screening and prevention of venous thromboembolism in critically ill patients: a decision analysis and economic evaluation. Am J Respir Crit Care Med. 2011 Dec 1;184(11):1289-98. doi: 10.1164/rccm.201106-1059OC [MEDLINE]
  • LIFENOX: Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. doi: 10.1056/NEJMoa1111288 [MEDLINE]
  • Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007557. doi: 10.1002/14651858.CD007557.pub2 [MEDLINE]
  • DVT Surveillance Program in the ICU: Analysis of Cost-Effectiveness. PLoS One. 2014 Sep 30;9(9):e106793. doi: 10.1371/journal.pone.0106793. eCollection 2014 [MEDLINE]
  • Cost-effectiveness of Dalteparin vs Unfractionated Heparin for the Prevention of Venous Thromboembolism in Critically Ill Patients. JAMA. 2014 Nov 1. doi: 10.1001/jama.2014.15101 [MEDLINE]

Upper Extremity DVT

  • The long term clinical course of acute deep vein thrombosis of the arm: prospective cohort study. BMJ. 2004;329:484-5 [MEDLINE]
  • Upper extremity DVT in oncological patients: analysis of risk factors. Data from the RIETE registry. Exp Oncol. 2006;28:245-7
  • Upper extremity deep venous thrombosis. Semin Thromb Hemost. 2006;32:729-36 [MEDLINE]
  • Current perspective of venous thrombosis in the upper extremity. J Thromb Haemost. 2008;6:1262-6 [MEDLINE]
  • Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review. J Thromb Haemost. 2010;8:684-92 [MEDLINE]
  • Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study. Ann Intern Med. 2014 Apr 1;160(7):451-7. doi: 10.7326/M13-2056 [MEDLINE]

Treatment

General Treatment

  • Use of Glucocorticoids and Risk of Venous Thromboembolism: A Nationwide Population-Based Case-Control Study. JAMA Intern Med. 2013 Apr 1:1-1 [MEDLINE]
  • Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism. J Med Econ. 2014 Jan;17(1):52-64. doi: 10.3111/13696998.2013.858634. Epub 2013 Nov 14 [MEDLINE]
  • Comparison of differences in medical costs when new oral anticoagulants are used for the treatment of patients with non-valvular atrial fibrillation and venous thromboembolism vs warfarin or placebo in the US. J Med Econ. 2015 Jun;18(6):399-409. doi: 10.3111/13696998.2015.1007210. Epub 2015 Feb 9 [MEDLINE]
  • Cost-effectiveness analysis of treatment of venous thromboembolism with rivaroxaban compared with combined low molecular weight heparin/vitamin K antagonist. Thromb J. 2015 Jun 11;13:20. doi: 10.1186/s12959-015-0051-3. eCollection 2015 [MEDLINE]
  • Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]
  • Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest. 2016,(): doi:10.1016/j.chest.2015.12.029 [MEDLINE]

Inferior Vena Cava Filter

  • A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis: Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409-415 [MEDLINE]
  • PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112(3):416-422 [MEDLINE]
  • A population-based study of inferior vena cava filters in patients with acute venous thromboembolism. Arch Intern Med. 2010;170(16): 1456-1462 [MEDLINE]
  • Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124(7):655-661 [MEDLINE]
  • PREPIC2 Trial. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015 Apr 28;313(16):1627-35. doi: 10.1001/jama.2015.3780 [MEDLINE]

Embolectomy

  • Pulmonary embolectomy: a 20-year experience at one center. Ann Thorac Surg 1991; 51:232-236
  • Medical compared with surgical treatment for massive pulmonary embolism. Lancet 1994; 343:565-577

Thrombolytics

  • Urokinase pulmonary embolism trial. A national cooperative study. Circulation 1973; 47,48 (suppl 2):1-108
  • Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 34:507-511
  • Thrombolytic therapy for pulmonary embolism. Cochrane Database System Rev. 2009;(3): CD004437 [MEDLINE]
  • Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. doi: 10.1001/jama.2014.5990 [MEDLINE]
  • PEITHO Trial: Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097 [MEDLINE]
  • Systematic review and meta-analysis for thrombolysis treatment in patients with acute submassive pulmonary embolism. Patient Prefer Adherence. 2014;8:275-282 [MEDLINE]
  • Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med. 2014;174(9):1494-1501 [MEDLINE]
  • Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2015 Sep 30;9:CD004437. doi: 10.1002/14651858.CD004437.pub4 [MEDLINE]
  • Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]